The present invention relates to methods for the synthesis of xcex1-hydroxy-xcex2-amino acid and amide derivatives, and methods of using these intermediates in the synthesis of a variety of more complex peptidyl xcex1-ketoamides and xcex1-hydroxy-xcex2-amino carboxylic acid derivatives.
xcex1-Hydroxy-xcex2-aminocarboxylic acid and amide derivatives are found in a variety of natural products and pharmaceutical substances. Subunits incorporating the xcex1-hydroxy-xcex2-aminocarboxylic acid motif have been termed xe2x80x9cnorstatinexe2x80x9d derivatives, and serve as key intermediates for the synthesis of the general class of P1-xcex1-ketocarboxylic transition-state inhibitors of serine or cysteine proteases. Such inhibitors are finding increasing applications in medicine for the treatment of a diverse array of disease states including thrombosis, cancer, and osteoporosis. Towards this end, xcex1-hydroxy-xcex2-aminocarboxylic acid, ester and amide derivatives serve an important role as the most common precursors for the preparation of these xcex1-keto-carboxylic-acid-incorporating drug candidates.
Electrophilic xcex1-dicarbonyl compounds are regarded as interesting and highly reactive functional arrays which are capable of undergoing a myriad of transformations. Such chemical properties can be exploited in novel and therapeutically useful ways by strategically incorporating these reactive xcex1-ketocarboxylic moieties into a peptidic or peptidomimetic matrix. The xcex1-keto-carbonyl group is highly electropositive due to the presence of the adjoining electron-withdrawing amide functionality. Hence, it is highly reactive towards conventional biological nucleophiles encountered at the catalytic triad of a protease active site, including hydroxyl, thiol, and amino nucleophiles.
A prototypical serine protease substrate for which a suitable inhibitor is to be designed is Compound 1-1, depicted in FIG. 1A. The target site for this protease is composed of four amino acid residues: P3, P2, P1, P1xe2x80x2. In this and the derived ketoamide inhibitor structure 1-2, the notation P1, P2, . . . Pn denotes the position of a peptide residue relative to the scissile bond which is defined as P1-P1xe2x80x2 of the substrate undergoing cleavage (Schechter and Berger, Biochem. Biophys. Res. Commun. 1967, 27: 157-162).
Upon entering and docking into the active site of a serine or cysteine protease, the peptidic or peptidomimetic backbone portion Pn . . . Pnxe2x80x2 of target inhibitor 1-2 provides an array of important contact points which are stabilizing and energetically favorable. Such key geometric, hydrophobic, and electrostatic interactions help to bind the inhibitor to the protease, while the strategically positioned P1 xcex1-ketoamide function serves to inactivate the protease via formation of a slowly reversible covalent bond with the critical serine hydroxyl or cysteine thiol functions at the S1 site. The formation of such tetrahedral intermediates effectively ties up and, therefore, deactivates the active site, ultimately leading to inhibition of the enzyme.
Due to the highly stereospecific nature of several critical interactions at the enzyme active site, the relative and absolute stereochemistry of both P1-xcex1- and xcex2-positions has a profound effect on the overall biological activity and selectivity profiles of the target drugs, e.g. protease inhibitors, into which these motifs are incorporated. As a result, the stereospecific synthesis of these classes of compounds has received increasing attention over the past decade.
Several prominent examples have recently emerged that illustrate the variety and importance of the xcex1-hydroxy-xcex2-aminocarboxylic acid and amide derivatives (see FIGS. 1B to 1D). For instance, the natural product paclitaxel (Taxol(copyright)), a potent anticancer drug, features a biologically essential C-13 N-benzoyl-3-phenylisoserine side chain esterified to a secondary alcohol function. FIG. 1B depicts the N-benzoyl-3-phenylisoserine side chain. The natural product bestatin (structure depicted in FIG. 1C), also an xcex1-hydroxy-xcex2-amino amide derivative, is reported to possess anticancer, immune response modifier, as well as amino-peptidase B (AP-B), leucine aminopeptidase (LAP), and prolyl endopeptidase (PEP) enzyme inhibitory activities. Amastatin (structure depicted in FIG. 1D), a related peptidic natural product, is reported to demonstrate amino-peptidase A (AP-A) and leucine aminopeptidase enzyme inhibitory properties.
xcex1-Hydroxy-xcex2-amino amide derivatives also are useful inhibitors of aspartyl proteases (see FIG. 2A). The promising synthetic HIV protease inhibitor Kynostatin (2-2) (Mimoto, et al., Chem. Pharm. Bull. 40(8): 2251-2253 (1992)) which incorporates an allophenylnorstatine (Apns) (2-1) moiety, is an xcex1-hydroxy-xcex2-amino amide derivative. Some synthetic renin inhibitors (2-4 and 2-5) feature the related cyclohexylnorstatine (Chns) residue (2-3) (see FIG. 2B) (Iizuka, et al., J. Med. Chem. 33: 2707-2714 (1990); Dhanoa, et al., Tetrahedron Letters, 33(13): 1725-1728 (1992)). In the HIV and renin inhibitors, the xcex1-hydroxy-xcex2-aminocarboxylic, or xe2x80x9cnorstatinexe2x80x9d, residue is employed as a hydroxymethyl carbonyl peptide bond isostere, which in turn serves as the P1-transition state mimic of peptide hydrolysis.
Inhibition of thrombin, a key terminal serine protease in the blood coagulation cascade, has been the subject of recent intensive investigation. Within the xcex1-hydroxy-xcex2-amino ester group of compounds (3-1), the thrombin inhibitor BMS 181316 incorporates a P1-lysine derived xcex1-hydroxy-xcex2-aminoester residue (3-2) (see FIG. 3A). (Iwanowicz et al., Bioorganic and Medicinal Chemistry Letters, 2(12); 1607-1612 (1992)).
A variety of electrophilic P1-transition state compounds have been discovered and developed for use as thrombin inhibitors. From this general family of inhibitors, xcex1-ketoamide derivatives have figured prominently with regard to outstanding inhibitory potency. Such peptidomimetic inhibitors have been efficacious both in vitro and in vivo, for example, in animal models of small vein thrombosis and deep vein thrombosis (DVT). By elaboration of xcex1-hydroxyhomoarginine precursors (3-3 of FIG. 3B), a series of P1-ketoargininamide derivatives were prepared which expressed potent thrombin inhibitory properties (see, e.g., U.S. Pat. Nos. 5,371,072; 5,597,804; 5,656,600; and 5,670,479). A large number of variations in the P2-P4 residues as well as P1xe2x80x2 residues were investigated which provided a family of active and selective thrombin inhibitors. See, e.g., 3-4 of FIG. 3B.
In a related class of protease inhibitors, P1-ketonorvalinamide peptide derivatives showed high inhibitory activity against a family of intracellular calpains. The calpains are cysteine proteases responsible for neurodegeneration which accompanies either global or focal cerebral ischemia. Such neutral P1-ketoamide inhibitors were prepared from 2-hydroxy-3-aminohexanoic acid (3-5 of FIG. 3C). Several related neutral, lipophilic P1-ketoamide derivatives have found application as inhibitors for a broad range of cysteine protease enzymes. See, e.g., 3-6 of FIG. 3C. (Harbeson et al., J. Med. Chem., 37:2918-2929 (1994)).
There have been reports describing the synthesis of peptidal xcex1-ketoamide derivatives which are useful as enzyme inhibitors. The most widely utilized method of preparation is based upon a conventional multi-step solution phase approach and is outlined in FIG. 4A/Scheme 1. (See U.S. Pat. Nos. 5,371,072; 5,597,804; 5,656,600; and 5,670,479; Semple et al., Bioorg. Med. Chem. Lett. 7:315 (1997); Maryanoff et al., J. Am. Chem. Soc. 117:1225 (1995); and Harbeson et al., J. Med. Chem. 37:2918 (1994).) A protected amino acid derivative 4-2 (PG denotes protecting group) is elaborated via known methods to the protected xcex1-aminoaldehyde derivative 4-3. The xcex1-hydroxy-xcex2-amino ester intermediate 4-4 is prepared from 4-3 via a four-step process. Thus, reaction of 4-3 with saturated aqueous sodium bisulfite produces the corresponding bisulfite addition adduct. Treatment of the adduct with aqueous basic potassium cyanide generates a cyanohydrin intermediate. Hydrolysis of the cyanohydrin intermediate is usually accomplished with a mineral acid such as hydrochloric acid at about reflux temperature. Due to the rather drastic reaction conditions, this process generally affords the fully deprotected xcex1-hydroxy-xcex2-amino acid intermediate. Esterification of this material with a suitable alcohol like methanol under standard acid-catalyzed conditions then affords the xcex1-hydroxy-xcex2-amino ester intermediate 4-4.
The amino group of 4-4 is reprotected, for example, as the N-Boc derivative by using Boc anhydride under mildly basic conditions in a two-phase solvent system, typically consisting of tetrahydrofuran and water, and affords 4-5 which is now suitably protected to allow for efficient subsequent peptide coupling reactions. Hydrolysis of the ester group of 4-5 with an aqueous alkali hydroxide such as lithium hydroxide and acidification affords a carboxylic acid intermediate. Coupling of a P1xe2x80x2 aminoester intermediate with this intermediate carboxylic acid via standard peptide coupling reagents produces 4-6.
The P1-Boc amino-protecting group is then cleaved off by n acid catalyst such as trifluoroacetic acid or hydrogen chloride and the resultant amine salt is elaborated via standard peptide coupling protocols in a reiterative fashion to afford Pn . . . P1 peptidic P1-xcex1-hydroxyamide derivative. Optional orthogonal deprotection of the peptide side chains followed by a final oxidation step affords the target peptidal xcex1-ketoamide derivative 4-1.
An alternative and milder route to peptidal xcex1-ketoamide derivatives which has received attention but generally proceeds in modest to poor overall yields is depicted in FIG. 4B/Scheme 2. (See, Iwanowicz et al., Bioorg. Med. Chem. Lett. 2:1607 (1992); Schreiber et al., J. Am. Chem. Soc. 114:6570 (1992).) The reaction sequence commences by reaction of the blocked aminoaldehyde 4-7 with the lithium salt of ethyl orthothioformate at low temperatures of about xe2x88x9278xc2x0 C. to xe2x88x9220xc2x0 C. A mercuric chloride-mercuric oxide assisted cleavage of the resultant intermediate in methanolic milieu then generates intermediate 4-8 whose amino function may be protected by a variety of groups, including the Boc group discussed for 4-5 prepared above by the first route. This intermediate can be hydrolyzed to the corresponding carboxylic acid, coupled with a suitable P1xe2x80x2 amino acid residue and elaborated as described above to afford a peptidal xcex1-ketoamide target 4-1.
Other protocols which are finding increasing popularity adopt this methodology and utilize solid phase synthesis technology. (See, e.g., Abeles et al., Proc. Natl. Acad. Sci. (USA) 92:6738 (1995).)
By possessing a divalent carbon atom, the isonitrile functional group shows unusual reactivity profiles and, as such, has shown the propensity to participate in multiple-component reactions. In 1921, Passerini described an unusual and potentially highly useful three-component reaction of an isonitrile R1NC (5-1) with a carbonyl compound such as an aldehyde R2CHO (5-2) and a carboxylic acid derivative R3CO2H (5-3). As depicted in FIG. 5/Scheme 3, the three components assemble to generate an intermediate 5-4. Upon subsequent acyl shift and proton transfer, a considerably more complex xcex1-acyloxycarboxamide derivative 5-5 is obtained. Such a reaction takes place under very mild conditions, typically in the temperature range of about xe2x88x9278xc2x0 C. to about 80xc2x0 C., optionally in the presence of suitable solvents including methanol or dichloromethane.
Since its discovery, the so-called Passerini reaction has been studied rather sporadically and no definitive systematic investigations which might lead to generally useful preparative protocols appear to have been reported. Various inter- and intra-molecular variants have been described, but these reports failed to provide a generally useful synthetic method. (See generally, Passerini, Gazz. Chim. Ital. 51:126 (1921); Passerini and Ragni, Gazz. Chim. Ital. 61:964 (1931); Ugi et al., in xe2x80x9cIsonitrile Chemistryxe2x80x9d, Chapter 7, Academic Press, New York, N.Y. (1971). For intramolecular version, see Falck and Manna, Tet. Lett. 22:619 (1981). For acid-catalyzed versions, see, Hagedorn and Eholzer, Chem. Ber. Jahrg. 98:936 (1965); Kaiser et al., J. Med. Chem. 20:1258 (1977); and Lumma et al., J. Org. Chem. 46:3668 (1981). For Lewis-acid catalyzed versions to produce xcex1-hydroxyamides directly, see, Muller and Zeeh, Liebigs Ann. Chem. 696:72 (1966); Muller and Zeeh, Liebigs Ann. Chem. 715:47 (1968); Mukaiyama et al., Chem. Lett. 1994 1457-1458 (1994); Seebach and Schiess, Helv. Chim. Acta 66:1618 (1983); Seebach et al., Chem. Ber. 121:507 (1988); Floriani et al., Organometallics 12:2726 (1993). For Eurystatin A total synthesis, see, Schmidt and Weinbrenner, J. Chem. Soc. Chem. Commun. 1994 1003 (1994).)
The present invention provides new methods for the synthesis of xcex1-hydroxy-xcex2-aminoamide derivatives and xcex1-hydroxyl-xcex2-amino carboxylic acid derivatives, which can be used as intermediates in the synthesis of known and new compounds incorporating an xcex1-ketoamide bond.
The present invention provides novel methods for the synthesis of xcex1-hydroxyl-xcex2-amino acid and amide derivatives. These derivatives are useful as intermediates for synthesis of peptidyl xcex1-ketoamides and xcex1-hydroxyl-xcex2-amino carboxylic acid derivatives which are useful as inhibitors of certain proteases, including serine and cysteine proteases.
These methods involve reacting together an N-terminally blocked (protected) amino aldehyde with an isonitrile and a carboxylic acid to give an amino xcex1-acyloxy carboxamide. The acyloxy group may be removed to give the derivative. Alternatively, the protecting group is removed and acyl shift takes place to give the derivative.
Among other factors, the present invention provides novel methods that allow for a more direct synthetic route with improved yields of compounds which incorporate an xcex1-hydroxyl-xcex2-amino ester or an xcex1-ketoamide moiety. As noted in the Background and Introduction to the Invention, a number of compounds having an xcex1-hydroxyl-xcex2-amino ester or xcex1-ketoamide moiety have been reported as useful as inhibitors of certain proteases. The methods of the present invention provide an improved synthetic route to intermediates for the end target compounds, with economy of synthesis, namely fewer synthetic steps, improved yields, less consumption of reagents and fewer side products than are obtained following conventional synthetic routes.
Accordingly, according to one aspect of the invention, provided are methods for making an xcex1-hydroxyl-xcex2-amino carboxylic acid of formula (A): 
wherein
(i) Rx is xe2x80x94PG or xe2x80x94C(O)R3 where PG is a protecting group;
(ii)
(a) R1, R2 and R3 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, cycloalkenyl of 5 to about 12 carbon atoms, and alkynyl 3 to about 12 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from Y1, Y2 and/or Y3; aryl of about 5 to about 14 carbon atoms which is optionally mono-, di- or tri- substituted with Y1, Y2, and/or Y3; heteroaryl of about 5 to about 14 ring atoms, with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono-, di-, tri- substituted with Y1, Y2 and/or Y3; aralkyl of about 6 to about 18 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3; and heteroaralkyl of about 5 to about 18 carbon atoms having about 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono, di- or tri-substituted on the ring with Y1, Y2 and/or Y3;
(b) alternatively R1 is xe2x80x94CH(R5)C(O)W1 or a peptidyl substituent of the formula xe2x80x94(Xaa1)nW2, wherein R5 is hydrogen, alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, aryl of 5 to about 14 carbon atoms, or aralkyl of about 7 to about 15 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from hydroxy, sulfhydryl, alkylthio, carboxyl, amide, amino alkylamino, indolyl, 3-N-formylindolyl, benzyloxy, halobenzyloxy, guanidino, nitroguanidino or imidazolyl optionally substituted with alkoxyalkyl; W1 and W2 are independently selected from xe2x80x94OH, xe2x80x94OZ1, xe2x80x94SH, xe2x80x94SZ1, xe2x80x94NH2, xe2x80x94NHZ1 and xe2x80x94NZ1Z2; each Xaa1 is an independently selected amino acid residue and n is an integer from 1 to 10; or
(c) alternatively R3C(O)xe2x80x94 is W1CH(R5)C(O)xe2x80x94 or R4 wherein R4 is a peptide substituent of the formula Z1X(Xaa2)rxe2x80x94 wherein each Xaa2 is an independently selected amino acid residue, r is an integer from 1 to 10 and X is xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94OC(O)xe2x80x94, or a direct link;
(iii) each Y1, Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CF3, xe2x80x94CH(CF3)2, xe2x80x94OCF3, xe2x80x94OCF2H, xe2x80x94OCF2CF3, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NHZ1, xe2x80x94OC(O)NZ1Z2, xe2x80x94NHC(O)Z1, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NHZ1, xe2x80x94NHC(O)NHZ1Z2, xe2x80x94C(O)OH, xe2x80x94C(O)OZ1, xe2x80x94C(O)NH2, xe2x80x94C(O)NHZ1, xe2x80x94C(O)NZ1Z2, xe2x80x94P(O)3H2, xe2x80x94P(O)3(Z1)2, xe2x80x94S(O)3H, xe2x80x94S(O)mZ1, xe2x80x94Z1, xe2x80x94OZ1, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHZ1, xe2x80x94NZ1Z2, and xe2x80x94S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5; and
(iv) each Z1 and Z2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms; comprising the steps:
(a) reacting a protected amino-aldehyde of the formula PGNHCH(R2)CHO, an isonitrile of the formula R1NC and a carboxy compound of the formula YCO2H wherein Y is CF3 or R3 to give an aminoacyloxycarboxamide compound of formula (B): 
xe2x80x83and
(b)
(i) where Rx is PG, treating the amino acyloxycarboxamide intermediate from step (a) under acyloxy group removing conditions to give said compound of formula (A); or
(ii) where Rxxe2x80x94C(O)R3, treating the amino acyloxycarboxamide intermediate from step (a) under PG group removing conditions which include a pH of about 6 to about 9 to give said compound of formula (A).
According to one preferred embodiment Rx is PG. According to one aspect of this embodiment, Y is trifluoromethyl. Preferred acyloxy group removing conditions include extractive aqueous procedures. Such procedures preferably partition organic products and by-products between organic and aqueous phases to allow easy separation of a desired organic product from by-products. It is especially preferred to include a mild organic base in step (a). Suitable mild organic bases include pyridine and its alkyl derivatives. According to an alternate aspect of this embodiment, Y is R3. Preferred acyloxy group removing conditions include selective hydrolysis with an alkali metal alkoxide.
According to an alternate preferred embodiment of this aspect of the invention, Rx is xe2x80x94C(O)R3. Suitable PG group removal conditions depend on the PG group and are summarized hereinbelow in the Detailed Description of the Invention.
Optionally, the methods of the invention may further comprise a step wherein the derivative of formula (A) is subjected to oxidation conditions so that the xcex1-hydroxy group is oxidized to a carbonyl to give an xcex1-ketoamide derivative of formula (C): 
Suitable oxidizing conditions include use of EDC and DCA in DMSO and toluene, and those described hereinbelow in the Detailed Description of the Invention.
According to the present invention, a number of embodiments are provided. One group is directed to methods which employ trifluoroacetic acid (xe2x80x9cTFA Methodsxe2x80x9d) and another group is directed to methods which employ a carboxylic acid of formula R3COOH (xe2x80x9cComplex Methodsxe2x80x9d).
According to an aspect of the present invention which uses trifluoroacetic acid, provided are a group of embodiments termed herein xe2x80x9cTFA Methodsxe2x80x9d. Included within this group of embodiments is a method termed xe2x80x9cTFA Method Ixe2x80x9d which is a method of preparing an xcex1-hydroxyl-xcex2-amino acid derivative comprising the steps of
(a) contacting a blocked aminoaldehyde of the formula PGNHCH(R2)CHO with trifluoroacetic acid and an isoitrile compound of the formula R1NC in the presence of a mild organic base to give a transient amino acyloxy trifluoroacetate derivative; and
(b) treating the amino acyloxy trifluoroacetate derivative of step (a) under acyloxy removing conditions to give an xcex1-hydroxy-xcex2-amino amide derivative of formula (TFA-I): 
xe2x80x83wherein:
(i) PG is a protecting group; and
(ii)
(a) R1 and R2 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, cycloalkenyl of 5 to about 12 carbon atoms, and alkynyl 3 to about 12 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from Y1, Y2 and/or Y3; aryl of about 5 to about 14 carbon atoms which is optionally mono-, di- or tri- substituted with Y1, Y2 and/or Y3; heteroaryl of about 5 to about 14 ring atoms, with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono-, di-, tri- substituted with Y1, Y2 and/or Y3; aralkyl of about 6 to about 18 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3; and heteroaralkyl of about 5 to about 18 carbon atoms having about 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono, di- or tri-substituted on the ring with Y1, Y2 and/or Y3; or
(b) alternatively R1 is xe2x80x94CH(R5)C(O)W1, or a peptidyl substituent of the formula xe2x80x94(Xaa1)nW2, wherein R5 is hydrogen, alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, aryl of 5 to about 14 carbon atoms, or aralkyl of about 7 to about 15 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from hydroxy, sulfhydryl, alkylthio, carboxyl, amide, amino alkylamino, indolyl, 3-N-formylindolyl, benzyloxy, halobenzyloxy, guanidino, nitroguanidino or imidazolyl optionally substituted with alkoxyalkyl; W1 and W2 are independently selected from xe2x80x94OH, xe2x80x94OZ1, xe2x80x94SH, xe2x80x94SZ1, xe2x80x94NH2, xe2x80x94NHZ1 and xe2x80x94NZ1Z2; each Xaa1 is an independently selected amino acid residue and n is an integer from 1 to 10;
(iii) each Y1, Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CF3, xe2x80x94CH(CF3)2, xe2x80x94OCF3H, xe2x80x94OCF2CF3, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NHZ1, xe2x80x94OC(O)NZ1Z2, xe2x80x94NHC(O)Z1, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NHZ1, xe2x80x94NHC(O)NHZ1Z2, xe2x80x94C(O)OH, xe2x80x94C(O)OZ1, xe2x80x94C(O)NH2, xe2x80x94C(O)NHZ1, xe2x80x94C(O)NZ1Z2, xe2x80x94P(O)3H2, xe2x80x94P(O)3(Z1)2, xe2x80x94S(O)3H, xe2x80x94S(O)mZ1, xe2x80x94Z1, xe2x80x94OZ1, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHZ1, xe2x80x94NZ1Z2, and xe2x80x94S (O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5; and
(iv) and each Z1 and Z2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms.
According to a further aspect is provided a method termed xe2x80x9cTFA Method IIxe2x80x9d which further comprises (c) contacting the product (formula TFA-I) of step (b) of method TFA-1 with an acid reagent under hydrolytic conditions to give an xcex1-hydroxy-xcex2-amino acid of the formula (TFA-II) 
The present invention also provides a method termed xe2x80x9cTFA Method IIIxe2x80x9d which is a method of preparing an xcex1-ketoamide derivative of formula (TFA-III): 
wherein
(i) PG is a protecting group; and
(ii)
(a) R1 and R2 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, cycloalkenyl of 5 to about 12 carbon atoms, and alkynyl 3 to about 12 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from Y1, Y2 and/or Y3; aryl of about 5 to about 14 carbon atoms which is optionally mono-, di- or tri- substituted with Y1, Y2, and/or Y3; heteroaryl of about 5 to about 14 ring atoms, with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono-, di-, tri- substituted with Y1, Y2 and/or Y3; aralkyl of about 6 to about 18 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3; and heteroaralkyl of about 5 to about 18 carbon atoms having about 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono, di- or tri-substituted on the ring with Y1, Y2 and/or Y3; or
(b) alternatively R1 is xe2x80x94CH(R5)C(O)W1, or a peptidyl substituent of the formula xe2x80x94(Xaa1)nW2, wherein R5 is hydrogen, alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, aryl of 5 to about 14 carbon atoms, or aralkyl of about 7 to about 15 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from hydroxy, sulfhydryl, alkylthio, carboxyl, amide, amino alkylamino, indolyl, 3xe2x80x94N-formylindolyl, benzyloxy, halobenzyloxy, guanidino, nitroguanidino or imidazolyl optionally substituted with alkoxyalkyl; W1 and W2 are independently selected from xe2x80x94OH, xe2x80x94OZ1, xe2x80x94SH, xe2x80x94SZ1, xe2x80x94NH2, xe2x80x94NHZ1 and xe2x80x94NZ1Z2; each Xaa1 is an independently selected amino acid residue and n is an integer from 1 to 10;
(iii) each Y1, Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH (CH3)2, xe2x80x94CH2CF3, xe2x80x94CH(CF3)2, xe2x80x94OCF3, xe2x80x94OCF2H, xe2x80x94OCF2CF3, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NHZ1, xe2x80x94OC(O)NZ1Z2, xe2x80x94NHC(O)Z1, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NHZ1, xe2x80x94NHC(O)NHZ1Z2, xe2x80x94C(O)OH, xe2x80x94C(O)OZ1, xe2x80x94C(O)NH2, xe2x80x94C(O)NHZ1, xe2x80x94C(O)NZ1Z2, xe2x80x94P(O)3H2, xe2x80x94P(O)3(Z1)2, xe2x80x94S(O)3H, xe2x80x94S(O)mZ1, xe2x80x94Z1, xe2x80x94OZ1, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHZ1, xe2x80x94NZ1Z2, and xe2x80x94S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5; and
(iv) and each Z1 and Z2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms; comprising the steps of:
(a) contacting a blocked aminoaldehyde of the formula PGNHCG(R2)CHO with trifluoroacetic acid and an isonitrile compound of the formula R1NC in the presence of a mild organic base to give a transient amino acyloxy trifluoroacetate derivative;
(b) treating the amino acyloxy trifluoroacetate derivative of step (a) under acyloxy removing conditions or to give an xcex1-hydroxy-xcex2-amino amide derivative of formula (TFA-I); and
(c) treating the derivative from step (b) under oxidizing conditions to give an xcex1-ketoamide derivative of formula (TFA-III).
According to an alternate aspect of the present invention, provided is TFA Method IV which is directed to a method of preparing a semicarbazone-protected ketoamide derivative of formula (TFA-IV): 
wherein
(i) PG is a protecting group; and
(ii)
(a) R1 and R2 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, cycloalkenyl of 5 to about 12 carbon atoms, and alkynyl 3 to about 12 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from Y1, Y2 and/or Y3; aryl of about 5 to about 14 carbon atoms which is optionally mono-, di- or tri- substituted with Y1, Y2, and/or Y3; heteroaryl of about 5 to about 14 ring atoms, with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono-, di-, tri- substituted with Y1, Y2 and/or Y3; aralkyl of about 6 to about 18 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3; and heteroaralkyl of about 5 to about 18 carbon atoms having about 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono, di- or tri-substituted on the ring with Y1, Y2 and/or Y3; or
(b) alternatively R1 is xe2x80x94CH(R5)C(O)W1, or a peptidyl substituent of the formula xe2x80x94(Xaa1)nW2, wherein R5 is hydrogen, alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, aryl of 5 to about 14 carbon atoms, or aralkyl of about 7 to about 15 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from hydroxy, sulfhydryl, alkylthio, carboxyl, amide, amino alkylamino, indolyl, 3-N-formylindolyl, benzyloxy, halobenzyloxy, guanidino, nitroguanidino or imidazolyl optionally substituted with alkoxyalkyl; W1 and W2 are independently selected from xe2x80x94OH, xe2x80x94OZ1, xe2x80x94SH, xe2x80x94SZ1, xe2x80x94NH2, xe2x80x94NHZ1 and xe2x80x94NZ1Z2; each Xaa1 is an independently selected amino acid residue and n is an integer from 1 to 10;
(iii) each Y1, Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CF3, xe2x80x94CH(CF3)2, xe2x80x94OCF3, xe2x80x94OCF2H, xe2x80x94OCF2CF3, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NHZ1, xe2x80x94OC(O)NZ1Z2, xe2x80x94NHC(O)Z1, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NHZ1, xe2x80x94NHC(O)NHZ1Z2, xe2x80x94C(O)OH, xe2x80x94C(O)OZ1, xe2x80x94C(O)NH2, xe2x80x94C(O)NHZ1, xe2x80x94C(O)NZ1Z2, xe2x80x94P(O)3H2, xe2x80x94P(O)3(Z1)2, xe2x80x94S(O)3H, xe2x80x94S(O)mZ1, xe2x80x94Z1, OZ1, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHZ1, xe2x80x94NZ1Z2, and xe2x80x94S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5;
(iv) and each Z1 and Z2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms; and
(v) and xe2x80x94SC is a semicarbazone group of the formula xe2x80x94NHC(O)NHQ wherein Q is selected from the group consisting of hydrogen, alkyl of 1 to about 12 carbon atoms, alkenyl of 3 to about 12 carbon atoms, alkynyl of 3 to about 12 carbon atoms, aryl of 5 to about 18 carbon atoms, heteroaryl of 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur, di-arylalkyl and tri-arylalkyl;
comprising the step of contacting a xcex1-ketoamide derivative of formula (TFA-III) 
with a semicarbazide of the formula NH2NHC(O)NHQ under reactive conditions to give the semicarbazone derivative of formula (TFA-IV).
According to an aspect of the present invention termed xe2x80x9cTFA Method Vxe2x80x9d, provided is a method of preparing a peptidyl ketoamide of formula (TFA-V). 
wherein
(i)
(a) R1 and R2 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, cycloalkenyl of 5 to about 12 carbon atoms, and alkynyl 3 to about 12 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from Y1, Y2 and/or Y3; aryl of about 5 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3; heteroaryl of about 5 to about 14 ring atoms, with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono-, di-, tri-substituted with Y1, Y2 and/or Y3; aralkyl of about 6 to about 18 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3; and heteroaralkyl of about 5 to about 18 carbon atoms having about 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono, di- or tri-substituted on the ring with Y1, Y2 and/or Y3; or
(b) alternatively R1 is xe2x80x94CH(R5)C(O)W1, or a peptidyl substituent of the formula xe2x80x94(Xaa1)nW2, wherein R5 is hydrogen, alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, aryl of 5 to about 14 carbon atoms, or aralkyl of about 7 to about 15 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from hydroxy, sulfhydryl, alkylthio, carboxyl, amide, amino alkylamino, indolyl, 3xe2x80x94N-formylindolyl, benzyloxy, halobenzyloxy, guanidino, nitroguanidino or imidazolyl optionally substituted with alkoxyalkyl; W1 and W2 are independently selected from xe2x80x94OH, xe2x80x94OZ1, xe2x80x94SH, xe2x80x94SZ1, xe2x80x94NH2, xe2x80x94NHZ1 and xe2x80x94NZ1Z2; and each Xaa1 is an independently selected amino acid residue and n is an integer from 1 to 10;
(iii) each Y1, Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CF3, xe2x80x94CH(CF3)2, xe2x80x94OCF3, xe2x80x94OCF2H, xe2x80x94OCF2CF3, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NHZ1, xe2x80x94OC(O)NZ1Z2, xe2x80x94NHC(O)Z1, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NHZ1, xe2x80x94NHC(O)NHZ1Z2, xe2x80x94C(O)OH, xe2x80x94C(O)OZ1, xe2x80x94C(O)NH2, xe2x80x94C(O)NHZ1, xe2x80x94C(O)NZ1Z2, xe2x80x94P(O)3H2, xe2x80x94P(O)3(Z1)2, xe2x80x94S(O)3H, xe2x80x94S(O)mZ1, xe2x80x94Z1, xe2x80x94OZ1, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHZ1, xe2x80x94NZ1Z2, and xe2x80x94S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5, and each Z1 and Z2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms; and
(iv) R4 is Z1xe2x80x94Xxe2x80x94(Xaa2)rxe2x80x94 wherein X is xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)xe2x80x942, xe2x80x94OC(O)xe2x80x94 or a direct link, each Xaa2 is an independently selected amino acid residue and r is an integer from 1 to 10; comprising the steps of:
(a) removing protecting group PG from a protected xcex1-ketoamide derivative of formula (TFA-III) 
xe2x80x83wherein PG is a protecting group: and
(b) contacting the deprotected xcex1-ketoamide derivative from step (a) with a compound of the formula R4-LG, wherein LG is a leaving group, under coupling conditions to form an intermediate of the formula (TFA-V).
An alternate aspect of the present invention provides a group of embodiments of the present invention termed xe2x80x9cComplex Methodsxe2x80x9d. These Complex Methods employ a carboxylic acid of the formula R3COOH.
Accordingly, a method termed xe2x80x9cComplex Method Ixe2x80x9d is directed to a method of preparing an xcex1-hydroxy-xcex2-aminoamide derivative of the formula (CI) 
wherein
(i)
(a) R1, R2 and R3 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, cycloalkenyl of 5 to about 12 carbon atoms, and alkynyl 3 to about 12 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from Y1, Y2 and/or Y3; aryl of about 5 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3; heteroaryl of about 5 to about 14 ring atoms, with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono-, di-, tri-substituted with Y1, Y2 and/or Y3; aralkyl of about 6 to about 18 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3; and heteroaralkyl of about 5 to about 18 carbon atoms having about 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono, di- or tri-substituted on the ring with Y1, Y2 and/or Y3;
(b) alternatively R1 is xe2x80x94CH(R5)C(O)W1 or a peptidyl substituent of the formula xe2x80x94(Xaa1)nW2, wherein R5 is hydrogen, alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, aryl of 5 to about 14 carbon atoms, or aralkyl of about 7 to about 15 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from hydroxy, sulfhydryl, alkylthio, carboxyl, amide, amino alkylamino, indolyl, 3-N-formylindolyl, benzyloxy, halobenzyloxy, guanidino, nitroguanidino or imidazolyl optionally substituted with alkoxyalkyl; W1 and W2 are independently selected from xe2x80x94OH, xe2x80x94OZ1, xe2x80x94SH, xe2x80x94SZ1, xe2x80x94NH2, xe2x80x94NHZ1 and xe2x80x94NZ1Z2; each Xaa1 is an independently selected amino acid residue and n is an integer from 1 to 10; or
(c) alternatively R3C(O)xe2x80x94 is W1CH(R5)C(O)xe2x80x94 or R4 wherein R4 is a peptide substituent of the formula Z1X(Xaa2)rxe2x80x94 wherein each Xaa2 is an independently selected amino acid residue, r is an integer from 1 to 10 and X is xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94OC(O)xe2x80x94, or a direct link;
(ii) each Y1, Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CF3, xe2x80x94CH(CF3)2, xe2x80x94OCF3, xe2x80x94OCF2H, xe2x80x94OCF2CF3, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NHZ1, xe2x80x94OC(O)NZ1Z2, xe2x80x94NHC(O)Z1, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NHZ1, xe2x80x94NHC(O)NHZ1Z2, xe2x80x94C(O)OH, xe2x80x94C(O)OZ1, xe2x80x94C(O)NH2, xe2x80x94C(O)NHZ1, xe2x80x94C(O)NZ1Z2, xe2x80x94P(O)3H2, xe2x80x94P(O)3(Z1)2, xe2x80x94S(O)3H, xe2x80x94S(O)mZ1, xe2x80x94Z1, xe2x80x94OZ1, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHZ1, xe2x80x94NZ1Z2, and xe2x80x94S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5; and
(iii) each Z1 and Z2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms; comprising the steps of:
(a) reacting an N-terminally blocked aminoaldehyde of the formula PGNHCH(R2)CHO, wherein PG is a protecting group, with an isonitrile of the formula R1NC, and a carboxylic acid of the formula R3CO2H in solvent to give an amino xcex1-acyloxycarboxamide derivative of the formula 
(b) removing protecting group PG from the amino xcex1-acyloxycarboxamide derivative from step (a) under PG group removing conditions which include a pH of about 6 to about 9 thereby effecting acyl migration to give an xcex1-hydroxy-xcex2-aminoamide derivative of formula (CI).
According to a further aspect termed xe2x80x9cComplex Method IIxe2x80x9d, the present invention provides a method of preparing an xcex1-ketoamide derivative of formula (CII) 
wherein
(i)
(a) R1, R2 and R3 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, cycloalkenyl of 5 to about 12 carbon atoms, and alkynyl 3 to about 12 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from Y1, Y2 and/or Y3; aryl of about 5 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3; heteroaryl of about 5 to about 14 ring atoms, with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono-, di-, tri-substituted with Y1, Y2 and/or Y3; aralkyl of about 6 to about 18 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3; and heteroaralkyl of about 5 to about 18 carbon atoms having about 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono, di- or tri-substituted on the ring with Y1, Y2 and/or Y3;
(b) alternatively R1 is xe2x80x94CH(R5)C(O)W1 or a peptidyl substituent of the formula xe2x80x94(Xaa1)nW2, wherein R5 is hydrogen, alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, aryl of 5 to about 14 carbon atoms, or aralkyl of about 7 to about 15 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from hydroxy, sulfhydryl, alkylthio, carboxyl, amide, amino alkylamino, indolyl, 3-N-formylindolyl, benzyloxy, halobenzyloxy, guanidino, nitroguanidino or imidazolyl optionally substituted with alkoxyalkyl; W1 and W2 are independently selected from xe2x80x94OH, xe2x80x94OZ1, xe2x80x94SH, xe2x80x94SZ1, xe2x80x94NH2, xe2x80x94NHZ1 and xe2x80x94NZ1Z2; each Xaa1 is an independently selected amino acid residue and n is an integer from 1 to 10; or
(c) alternatively R3C(O)xe2x80x94 is W1CH(R5)C(O)xe2x80x94 or R4 wherein R4 is a peptide substituent of the formula Z1X(Xaa2)rxe2x80x94 wherein each Xaa2 is an independently selected amino acid residue, r is an integer from 1 to 10 and X is xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94OC(O)xe2x80x94, or a direct link;
(ii) each Y1, Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CF3, xe2x80x94CH(CF3)2xe2x80x94OCF3, xe2x80x94OCF2H, xe2x80x94OCF2CF3, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NHZ1, xe2x80x94OC(O)NZ1Z2, xe2x80x94NHC(O)Z1, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NHZ1, xe2x80x94NHC(O)NHZ1Z2, xe2x80x94C(O)OH, xe2x80x94C(O)OZ1, xe2x80x94C(O)NH2, xe2x80x94C(O)NHZ1, xe2x80x94C(O)NZ1Z2, xe2x80x94P(O)3H2, xe2x80x94P(O)3(Z1)2, xe2x80x94S(O)3H, xe2x80x94S(O)mZ1, xe2x80x94Z1, xe2x80x94Z1, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHZ1, xe2x80x94NZ1Z2, and xe2x80x94S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5; and
(iii) each Z1 and Z2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms; comprising the steps of:
(a) reacting an N-terminally blocked aminoaldehyde of the formula PGNHCH(R2)CHO, wherein PG is a protecting group, with an isonitrile of the formula R1NC, and a carboxylic acid of the formula R3CO2H in solvent to give an amino xcex1-acyloxycarboxamide derivative of the formula (CIA) 
(b) removing protecting group PG from the amino xcex1-acyloxycarboxamide derivative from step (a) under PG group removing conditions which include a pH of about 6 to about 9 thereby effecting acyl migration to give an xcex1-hydroxy-xcex2-aminoamide derivative of formula (CI); and
(c) treating the derivative of formula (CI) from step (b) under oxidizing conditions to give an xcex1-ketoamide derivative of formula (CII).
Another further aspect of the present invention is termed xe2x80x9cComplex Method IIIxe2x80x9d and provides a method of preparing a semi-carbazone protected ketoamide derivative of formula (CIII) using an xcex1-ketoamide of formula (CII). Accordingly, Complex Method III is directed to a method of preparing a semi-carbazone protected ketoamide derivative of formula (CIII): 
wherein
(i)
(a) R1, R2 and R3 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, cycloalkenyl of 5 to about 12 carbon atoms, and alkynyl 3 to about 12 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from Y1, Y2 and/or Y3; aryl of about 5 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3; heteroaryl of about 5 to about 14 ring atoms, with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono-, di-, tri-substituted with Y1, Y2 and/or Y3; aralkyl of about 6 to about 18 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3; and heteroaralkyl of about 5 to about 18 carbon atoms having about 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono, di- or tri-substituted on the ring with Y1, Y2 and/or Y3;
(b) alternatively R1 is xe2x80x94CH(R5)C(O)W1 or a peptidyl substituent of the formula xe2x80x94(Xaa1)nW2, wherein R5 is hydrogen, alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, aryl of 5 to about 14 carbon atoms, or aralkyl of about 7 to about 15 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from hydroxy, sulfhydryl, alkylthio, carboxyl, amide, amino alkylamino, indolyl, 3-N-formylindolyl, benzyloxy, halobenzyloxy, guanidino, nitroguanidino or imidazolyl optionally substituted with alkoxyalkyl; W1 and W2 are independently selected from xe2x80x94OH, xe2x80x94OZ1, xe2x80x94SH, xe2x80x94SZ1, xe2x80x94NH2, xe2x80x94NHZ1 and xe2x80x94NZ1Z2; each Xaa1 is an independently selected amino acid residue and n is an integer from 1 to 10; or
(c) alternatively R3C(O)xe2x80x94 is W1CH(R5)C(O)xe2x80x94 or R4 wherein R4 is a peptide substituent of the formula Z1X(Xaa2)rxe2x80x94 wherein each Xaa2 is an independently selected amino acid residue, r is an integer from 1 to 10 and X is xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94OC(O)xe2x80x94, or a direct link;
(ii) each Y1, Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CF3, xe2x80x94CH(CF3)2, xe2x80x94OCF3, xe2x80x94OCF2H, xe2x80x94OCF2CF3, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NHZ1, xe2x80x94OC(O)NZ1Z2, xe2x80x94NHC(O)Z1, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NHZ1, xe2x80x94NHC(O)NHZ1Z2, xe2x80x94C(O)OH, xe2x80x94C(O)OZ1, xe2x80x94C(O)NH2, xe2x80x94C(O)NHZ1, xe2x80x94C(O)NZ1Z2, xe2x80x94P(O)3H2, xe2x80x94P(O)3(Z1)2, xe2x80x94S(O)3H, xe2x80x94S(O)mZ1, xe2x80x94Z1, xe2x80x94Z1, OZ1, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHZ1, xe2x80x94NZ1Z2, and xe2x80x94S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5;
(iii) each Z1 and Z2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms; and
(iv) SC is xe2x80x94NHCONHQ wherein Q is selected from the group consisting of hydrogen, alkyl of 1 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, alkynyl of 3 to about 12 carbon atoms, aryl of 5 to about 18 carbon atoms, heteroaryl of 5 to about 18 ring atoms with the ring atoms selected from carbon atoms and heteroatoms wherein the heteroatoms are selected from oxygen, nitrogen and sulfur, aralkyl, di-arylalkyl and tri-arylalkyl; which comprises treating a compound of formula (CII) prepared by Complex Method II with a semicarbazide of the formula NH2NHCONHQ under conditions permitting formation of a semicarbazone-protected ketoamide derivative of formula (CIII).
An alternate aspect of the present invention termed xe2x80x9cComplex Method IVxe2x80x9d, provides a method of preparing a peptidyl ketoamide of formula (CIV): 
wherein
(i) R1 is xe2x80x94CH(R5)C(O)W1 or a peptidyl substituent of the formula xe2x80x94(Xaa1)nW2, wherein R5 is hydrogen, alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, aryl of 5 to about 14 carbon atoms, or aralkyl of about 7 to about 15 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from hydroxy, sulfhydryl, alkylthio, carboxyl, amide, amino alkylamino, indolyl, 3-N-formylindolyl, benzyloxy, halobenzyloxy, guanidino, nitroguanidino or imidazolyl optionally substituted with alkoxyalkyl; W1 and W2 are independently selected from xe2x80x94OH, xe2x80x94OZ1, xe2x80x94SH, xe2x80x94SZ1, xe2x80x94NH2, xe2x80x94NHZ1 and xe2x80x94NZ1Z2; each Xaa1 is an independently selected amino acid residue and n is an integer from 1 to 10;
(ii) R2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, cycloalkenyl of 5 to about 12 carbon atoms, and alkynyl 3 to about 12 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from Y1, Y2 and/or Y3; aryl of about 5 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3; heteroaryl of about 5 to about 14 ring atoms, with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono-, di-, tri-substituted with Y1, Y2 and/or Y3; aralkyl of about 6 to about 18 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3; and heteroaralkyl of about 5 to about 18 carbon atoms having about 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono, di- or tri-substituted on the ring with Y1, Y2 and/or Y3;
(iii) R4 is a peptidyl substituent of the formula Z1X(Xaa2)rxe2x80x94 wherein each Xaa2 is an independently selected amino acid residue, r is an integer from 1 to 10 and X is xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94OC(O)xe2x80x94, or a direct link;
(iv) each Y1, Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CF3, xe2x80x94CH(CF3)2, xe2x80x94OCF3, xe2x80x94OCF2H, xe2x80x94OCF2CF3, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NHZ1, xe2x80x94OC(O)NZ1Z2, xe2x80x94NHC(O)Z1, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NHZ1, xe2x80x94NHC(O)NHZ1Z2, xe2x80x94C(O)OH, xe2x80x94C(O)OZ1, xe2x80x94C(O)NH2, xe2x80x94C(O)NHZ1, xe2x80x94C(O)NZ1Z2, xe2x80x94P(O)3H2, xe2x80x94P(O)3(Z1)2, xe2x80x94S(O)3H, xe2x80x94S(O)mZ1, xe2x80x94Z1, xe2x80x94OZ1, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHZ1, xe2x80x94NZ1Z2, N-morpholino, xe2x80x94S(CF2)qCF3, and xe2x80x94S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5; and
(v) each Z1 and Z2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms; comprising steps of:
(a) reacting an N-terminally blocked aminoaldehyde of the formula PGNHCH(R2)CHO, where PG is a protecting group, with an isonitrite of the formula R1NC and a peptidyl carboxylic acid of the formula R4OH in solvent to give a xcex2-amino xcex1-acyloxycarboxamide derivative of the formula: 
(b) removing protecting PG from the xcex2-amino xcex1-acyloxycarboxamide derivative from step (a) under PG removing conditions which include a pH of about 6 to about 9 to give an xcex1-hydroxy-xcex2-aminoamide derivative of the formula 
xe2x80x83and
(c) treating the xcex1-hydroxy-xcex2-aminoamide derivative from step (b) under oxidizing conditions to give a peptidyl ketoamide derivative of formula (CIV).
An additional aspect of the present invention termed xe2x80x9cComplex Method Vxe2x80x9d provides a method of preparing an xcex1-hydroxyl-xcex2-protected aminoamide derivative of formula (CV): 
comprising the steps of:
(a) reacting an N-terminally blocked aminoaldehyde of the formula PGNHCH(R2)CHO, an isonitrile of the formula R1NC, and a carboxylic acid of the formula R3CO2H in solvent to give an amino xcex1-acyloxycarboxamide of the formula: 
xe2x80x83and
(b) treating the amino xcex1-acyloxycarboxamide derivative and selective hydrolysis conditions to hydrolyze the xcex1-acyloxy group to a xcex1-hydroxy xcex2-protected aminoamide derivative of formula (CV),
wherein
(i) PG is a protecting group; and
(ii)
(a) R1, R2 and R3 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, cycloalkenyl of 5 to about 12 carbon atoms, and alkynyl 3 to about 12 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from Y1, Y2 and/or Y3; aryl of about 5 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3; heteroaryl of about 5 to about 14 ring atoms, with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono-, di-, tri-substituted with Y1, Y2 and/or Y3; aralkyl of about 6 to about 18 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3; and heteroaralkyl of about 5 to about 18 carbon atoms having about 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono, di- or tri-substituted on the ring with Y1, Y2 and/or Y3;
(b) alternatively R1 is xe2x80x94CH(R5)C(O)W1 or a peptidyl substituent of the formula xe2x80x94(Xaa1)nW2, wherein R5 is hydrogen, alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, aryl of 5 to about 14 carbon atoms, or aralkyl of about 7 to about 15 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from hydroxy, sulfhydryl, alkylthio, carboxyl, amide, amino alkylamino, indolyl, 3-N-formylindolyl, benzyloxy, halobenzyloxy, guanidino, nitroguanidino or imidazolyl optionally substituted with alkoxyalkyl; W1 and W2 are independently selected from xe2x80x94OH, xe2x80x94OZ1, xe2x80x94SH, xe2x80x94SZ1, xe2x80x94NH2, xe2x80x94NHZ1 and xe2x80x94NZ1Z2; each Xaa1 is an independently selected amino acid residue and n is an integer from 1 to 10; or
(c) alternatively R3C(O)xe2x80x94 is W1CH (R5)C(O)xe2x80x94 or R4 wherein R4 is a peptide substituent of the formula Z1X(Xaa2)rxe2x80x94 wherein each Xaa2 is an independently selected amino acid residue, r is an integer from 1 to 10 and X is xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94OC(O)xe2x80x94, or a direct link;
(iii) each Y1, Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CF3, xe2x80x94CH(CF3)2, xe2x80x94OCF3, xe2x80x94OCF2H, xe2x80x94OCF2CF3, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NHZ1, xe2x80x94OC(O)NZ1Z2, xe2x80x94NHC(O)Z1, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NHZ1, xe2x80x94NHC(O)NHZ1Z2, xe2x80x94C(O)OH, xe2x80x94C(O)OZ1, xe2x80x94C(O)NH2, xe2x80x94C(O)NHZ1, xe2x80x94C(O)NZ1Z2, xe2x80x94P(O)3H2, xe2x80x94P(O)3(Z1)2, xe2x80x94S(O)3H, xe2x80x94S(O)mZ1, xe2x80x94Z1, xe2x80x94OZ1, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHZ1, xe2x80x94NZ1Z2, N-morpholino, xe2x80x94S(CF2)qCF3, and xe2x80x94S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5; and
(iv) each Z1 and Z2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms.
Preferred selective hydrolysis conditions used for Complex Method V include an alkali metal alkoxide.
The present invention is also directed to certain novel xcex1-hydroxy-xcex2-amino acid and amide derivatives and xcex1-ketoamide derivatives prepared by the Methods described herein.
Definitions
In accordance with the present invention and as used herein, the following terms are defined to have the following meanings unless explicitly stated otherwise.
xe2x80x9cAcyl migrationxe2x80x9d or xe2x80x9cacyl shiftxe2x80x9d refers to the movement or transfer of an acyl moiety, i.e., R(CO)xe2x80x94, from one molecular position to another. In the context of this invention, acyl movement is usually from an oxygen atom to a nitrogen atom.
xe2x80x9cAlkali metal alkoxidexe2x80x9d refers to a basic reagent of the general formula MOR, where M is an alkali metal cation such as Li, Na, or K and typically R is methyl, ethyl, isopropyl or another simple lower alkyl group.
The term xe2x80x9calkenylxe2x80x9d refers to unsaturated aliphatic groups having at least one double bond.
The term xe2x80x9calkylxe2x80x9d refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic (including polycyclic) groups.
The terms xe2x80x9calkoxyxe2x80x9d and xe2x80x9calkoxylxe2x80x9d refer to a group having the formula, Rxe2x80x94Oxe2x80x94, wherein R is an alkyl group.
The term xe2x80x9calkoxycarbonylxe2x80x9d refers to xe2x80x94C(O)OR wherein R is alkyl.
The term xe2x80x9caralkenylxe2x80x9d refers to an alkenyl group substituted with an aryl group.
The term xe2x80x9caralkylxe2x80x9d refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, phenethyl, and the like, all of which may be optionally substituted.
The term xe2x80x9carylxe2x80x9d refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes a carbocyclic aryl, heterocyclic aryl and biarylgroups, all of which may be optionally substituted.
The term xe2x80x9caryloxyxe2x80x9d refers to a group having the formula, Rxe2x80x94Oxe2x80x94, wherein R is an aryl group.
The term xe2x80x9caralkoxyxe2x80x9d refers to a group having the formula, Rxe2x80x94Oxe2x80x94, wherein R is an aralkyl group.
The term xe2x80x9camino acidxe2x80x9d refers to both natural, unnatural amino acids in their D and L stereo isomers if their structures allow such stereoisomeric forms, and their analogs. Natural amino acids include alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Val). Unnatural amino acids include, but are not limited to azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2,4 diaminoisobutyric acid, demosine, 2,2xe2x80x2-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylglycine, N-methylisoleucine, N-methylvaline, norvaline, norleucine, ornithine and pipecolic acid. Amino acid analogs include the natural and unnatural amino acids which are chemically blocked, reversibly or irreversibly, or modified on their N-terminal amino group or their side-chain groups, as for example, methionine sulfoxide, methionine sulfone, S-(carboxymethyl)-cysteine, S-(carboxymethyl)-cysteine sulfoxide and S-(carboxymethyl)-cysteine sulfone.
The term xe2x80x9camino acid analogxe2x80x9d refers to an amino acid wherein either the C-terminal carboxy group, the N-terminal amino group or side-chain functional group has been chemically modified to another functional group. For example, aspartic acid-(beta-methyl ester) is an amino acid analog of aspartic acid; N-ethylglycine is an amino acid analog of glycine; or alanine carboxamide is an amino acid analog of alanine.
The term xe2x80x9camino acid residuexe2x80x9d refers to radicals having the structure: (1) xe2x80x94C(O)xe2x80x94Rxe2x80x94NHxe2x80x94, wherein R typically is xe2x80x94CH(Rxe2x80x2)xe2x80x94, wherein Rxe2x80x2 is H or a carbon containing substituent; 
wherein p is 1, 2 or 3 representing the azetidinecarboxylic acid, proline or pipecolic acid residues, respectively.
xe2x80x9cBiarylxe2x80x9d refers to phenyl substituted by carbocyclic or heterocyclic aryl as defined herein, ortho, meta or para to the point of attachment of the phenyl ring.
xe2x80x9cBrinexe2x80x9d refers to an aqueous saturated solution of sodium chloride.
xe2x80x9cCarbocyclic arylxe2x80x9d refers to aromatic groups wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and naphthyl groups, all of which may be optionally substituted. Suitable carbocyclic aryl groups include phenyl and naphthyl. Suitable substituted carbocyclic aryl groups include indene and phenyl substituted by one to two substituents such being advantageously lower alkyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, halogen, trifluoromethyl, difluoromethyl, nitro, and cyano. Substituted naphthyl refers to naphthyl, more preferably 1- or 2-naphthyl, substituted by 1 to 3 independently selected substituents.
xe2x80x9cCycloalkenylxe2x80x9d refers to a cyclic alkenyl group. Suitable cycloalkenyl groups include, for example, cyclopentenyl and cyclohexenyl.
xe2x80x9cCycloalkylxe2x80x9d refers to a cyclic alkyl group having at least one ring and includes polycyclic groups, including fused ring cyclic alkyl groups. Suitable cycloalkyl groups include, for example, cyclohexyl, cyclopropyl, cyclopentyl, and cycloheptyl.
xe2x80x9cCyclohexylmethylxe2x80x9d refers to a cyclohexyl group attached to CH2.
xe2x80x9cFused carbocyclicxe2x80x9d refers to a multicyclic fused carbocyclic ring having both aromatic and non-aromatic rings. Suitable fused carbocyclic rings include fluorenyl, tetralin and the like.
xe2x80x9cFused carbocyclic alkylxe2x80x9d refers to an alkyl group substituted with a fused carbocyclic ring moiety, preferably a multicyclic fused carbocyclic ring including both aromatic and non-aromatic rings. Suitable fused carbocyclic alkyl groups include fluorenylmethyl, and the like.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
xe2x80x9cHeteroaralkenylxe2x80x9d refers to an alkenyl group substituted with a heteroaryl, and includes those heterocyclic systems described in xe2x80x9cHandbook of Chemistry and Physicsxe2x80x9d, 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, Ohio. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Preferably the alkenyl group has from 2 to about 6 carbon atoms.
xe2x80x9cHeteroaralkylxe2x80x9d refers to an alkyl group substituted with a heteroaryl, such as picolyl, and includes those heterocyclic systems described in xe2x80x9cHandbook of Chemistry and Physicsxe2x80x9d, 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, OH. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Preferably the alkyl group has from 1 to about 6 carbon atoms.
xe2x80x9cHeteroarylxe2x80x9d refers to aryl groups having from 1 to 9 carbon atoms and the remainder of the ring atoms are heteroatoms, and includes those heterocyclic systems described in xe2x80x9cHandbook of Chemistry and Physicsxe2x80x9d, 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, Ohio. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroatoms include oxygen, nitrogen, and S(O)i, wherein i is 0, 1 or 2, and suitable heterocyclic aryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like.
xe2x80x9cHeterocycloxe2x80x9d refers to a reduced heterocyclic ring system comprised of carbon, nitrogen, oxygen and/or sulfur atoms, and includes those heterocyclic systems described in xe2x80x9cHandbook of Chemistry and Physicsxe2x80x9d, 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, Ohio. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems.
xe2x80x9cHeterocycloalkylxe2x80x9d refers to an alkyl group substituted with a heterocyclo group, and includes those heterocyclic systems described in xe2x80x9cHandbook of Chemistry and Physicsxe2x80x9d, 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, Ohio. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Preferably the alkyl group has from about 1 to about 6 carbon atoms.
The term xe2x80x9clowerxe2x80x9d referred to herein in connection with organic radicals or groups defines such radicals or groups with one and up to and including 5 carbon atoms, preferably up to and including 4 carbon atoms, and advantageously one or two carbon atoms. Such radicals or groups may be straight chain or branched chain.
xe2x80x9cPerfluoroalkylxe2x80x9d refers to an alkyl group which has every hydrogen replaced with fluorine.
xe2x80x9cPerfluoroalkylxe2x80x9d refers to an aryl group which has every hydrogen replaced with fluorine.
xe2x80x9cPerfluoroarylalkylxe2x80x9d refers to an aralkyl group in which every hydrogen on the aryl moiety is replaced with fluorine. xe2x80x9cPharmaceutically acceptable saltxe2x80x9d includes salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid. In practice the use of the salt form amounts to use of the base form. The compounds of the present invention are useful in both free base and salt form, with both forms being considered as being within the scope of the present invention.
xe2x80x9cAspartyl protease refers to a class of proteolytic enzymes which contain and utilize a P1-aspartic acid residue for a catalytic action, and as example refers to enzymes such as renin and HIV protease.
xe2x80x9cxcex1-Aminoaldehydexe2x80x9d refers to a reactive organic species of the general formula H2NC(R) (Rxe2x80x2)CHO, where R and Rxe2x80x2 can be H, alkyl, etc.
xe2x80x9cxcex1-Dicarbonyl compoundxe2x80x9d refers to a reactive organic species containing two contiguous carbonyl groups of the general formula R(CO)(CO)Rxe2x80x2, where R and Rxe2x80x2 can encompass the same or different substituents.
xe2x80x9cxcex1-Hydroxy-xcex2-aminocarboxylic acidxe2x80x9d refers to a functionalized carboxylic acid derivative of the general formula H2NC(R) (Rxe2x80x2)C(Rxe2x80x9d) (OH)CO2H, where R, Rxe2x80x2 and Rxe2x80x3 represent the same or different substituents.
xe2x80x9ca-Ketocarboxylicxe2x80x9d refers to a reactive, labile organic residue of the general formula R(CO)CO2Rxe2x80x2, where R and Rxe2x80x2 represent the same or different substituents, preferably not hydrogen. A ketocarboxylic acid is represented by a compound where Rxe2x80x2 is H. xe2x80x9cCalpainxe2x80x9d, an acronym for calcium-activated neutral protease, refers to an important member of the cysteine protease enzyme family which has been implicated in a variety of important disease states, including osteoporosis and cancer, neurodegeneration, stroke, Alzheimer""s disease, muscular dystrophy, platelet aggregation and inflammation.
xe2x80x9cCarboxamidexe2x80x9d refers to an organic functional group of the general formula RCON (R) (Rxe2x80x2), where R and Rxe2x80x2 represent the same or different substituents.
xe2x80x9cExtractive aqueous proceduresxe2x80x9d refer to procedures conventionally used in the chemical synthesis arts, including solution phase chemistry, which partition organic products and by-products between organic and aqueous phases to allow separation of a desired organic product from by-products.
xe2x80x9cHIVxe2x80x9d refers to Human Immunodeficiency Virus.
The terms xe2x80x9chydrolysisxe2x80x9d and xe2x80x9cselective hydrolysisxe2x80x9d refer to a cleavage reaction involving the addition of a molecule of water to an organic substrate.
xe2x80x9cHydrolytic work upxe2x80x9d refers to an aqueous extractive workup process which causes the hydrolysis of a functionality in an organic molecule.
xe2x80x9cInert organic solventxe2x80x9d refers to an unreactive solvent.
xe2x80x9cIsonitrilexe2x80x9d or xe2x80x9cisocyanidexe2x80x9d refer to a reactive functional group of the general formula Rxe2x80x94NC, where R represents an alkyl, aryl or other hydrocarbyl substituent.
xe2x80x9cKetoamidexe2x80x9d refers to the group xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94Nxe2x80x94.
xe2x80x9cLGxe2x80x9d refers to a leaving group.
xe2x80x9cMild organic basexe2x80x9d refers to a non-nucleophilic hindered organic base.
xe2x80x9cNorstatinexe2x80x9d refers to an xcex1-hydroxy-xcex2-amino acid derivative of the general formula H2NCH(R)CH(OH)CO2H where R is an alkyl, aryl or other hydrocarbyl substituent.
xe2x80x9cOxidationxe2x80x9d in the context of this invention, refers to a chemical process which essentially removes two electrons from the carbon atom from the species of formula xe2x80x94CH(OH)xe2x80x94 to produce a product of the formula xe2x80x94(Cxe2x95x90O)xe2x80x94. Formally, a change in the oxidation state of the carbon has increased, and the substrate has lost two hydrogen atoms.
xe2x80x9cPeptidexe2x80x9d refers to a compound having two or more amino acids linked to each other by amide bonds. Typically, peptides have up to about thirty amino acids.
xe2x80x9cPeptidomimeticxe2x80x9d or xe2x80x9cpeptide mimicxe2x80x9d refers to a synthetic organic molecule which resembles or mimics the structure of a peptide.
xe2x80x9cPGxe2x80x9d refers to a protecting group.
The terms xe2x80x9cprotectedxe2x80x9d and xe2x80x9creprotectingxe2x80x9d refer to the presence or addition of a protecting group, viz, the process of temporarily protecting or inactivating a normally reactive functional group so as to allow for conductance of chemical reactions in other parts of a molecule.
xe2x80x9cSemicarbazonexe2x80x9d refers to a derivative formed by the reaction of a semicarbazide with an aldehyde or ketone of the general formula R1(R2)Cxe2x95x90NNH(CO)NHRRxe2x80x2, where R1, R2, R, and Rxe2x80x2 can represent H, alkyl, aryl and other common organic groups.
xe2x80x9cSemicarbazidexe2x80x9d refers to a fundamental reagent of the formula H2NNH(CO)NH2 or H2NNH(CO)NRRxe2x80x2 which is known to react with a variety of electrophilic carbonyl compounds such as aldehydes and ketones. R and Rxe2x80x2 can represent H, alkyl, or other typical organic groups.
xe2x80x9cAcxe2x80x9d refers to acetyl.
xe2x80x9cAcmxe2x80x9d refers to acetamidomethyl.
xe2x80x9cAllocxe2x80x9d refers to allyloxycarbonyl.
xe2x80x9cBH3.THFxe2x80x9d refers to borane-tetrahydrofuran complex, a common reducing or hydroborating reagent.
xe2x80x9cBocxe2x80x9d refers to tert-butoxycarbonyl.
xe2x80x9c(Boc)2O refers to di-tert-butyl dicarbonate.
xe2x80x9cBomxe2x80x9d refers to benzyloxymethyl.
xe2x80x9cBzxe2x80x9d refers to benzoyl.
xe2x80x9cCbzxe2x80x9d refers to benzyloxycarbonyl or carbobenzyloxy.
xe2x80x9cCHOxe2x80x9d refers to a formyl group.
xe2x80x9c2-ClZxe2x80x9d refers to 2-chlorobenzyloxycarbonyl.
xe2x80x9cDCAxe2x80x9d or xe2x80x9cDCAAxe2x80x9d refers to dichloroacetic acid.
xe2x80x9cDCCxe2x80x9d refers to N,Nxe2x80x2-dicyclohexylcarbodiimide.
xe2x80x9cDCMxe2x80x9d refers to dichloromethane.
xe2x80x9cDIBALHxe2x80x9d or xe2x80x9c(i-Bu)2AlHxe2x80x9d refers to diisobutyl aluminum hydride.
xe2x80x9cDIEAxe2x80x9d or xe2x80x9cDIPEAxe2x80x9d refers to N,N-diisopropylethylamine.
xe2x80x9cDMFxe2x80x9d refers to N,N-dimethylformamide.
xe2x80x9cDMSOxe2x80x9d refers to dimethylsulfoxide.
xe2x80x9cDnpxe2x80x9d refers to 2,4-dinitrophenyl-.
xe2x80x9cdPscxe2x80x9d refers to diphenylmethyl semicarbazone protecting group.
xe2x80x9cEDCxe2x80x9d or xe2x80x9cEDC.HClxe2x80x9d refers to 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride salt.
xe2x80x9cEt3SiHxe2x80x9d refers to triethyl silane, a reducing agent.
xe2x80x9cEt3Nxe2x80x9d refers to triethylamine.
xe2x80x9cEtOAcxe2x80x9d refers to ethyl acetate.
xe2x80x9cFmocxe2x80x9d refers to 9-fluorenylmethyloxycarbonyl.
xe2x80x9cHCAxe2x80x9d refers to hydrocinnamoyl group.
xe2x80x9cHFxe2x80x9d refers to hydrogen fluoride.
xe2x80x9cHOBt refers to 1-hydroxybenzotriazole monohydrate.
xe2x80x9cIBCFxe2x80x9d refers to isobutyl chloroformate.
xe2x80x9cIBX reagentxe2x80x9d refers to an acronym for periodinane oxidizing reagent.
xe2x80x9cIPAxe2x80x9d refers to isopropyl alcohol or 2-propanol.
xe2x80x9cLAHxe2x80x9d refers to LiAlH4.
xe2x80x9cLTEPAxe2x80x9d refers to lithium tris[(3-ethyl-3-pentyl)oxy]aluminum hydride.
xe2x80x9cMBHA resinxe2x80x9d refers to methyl-benzhydrylamine resin.
xe2x80x9cMeO(Me)NHxe2x80x9d or xe2x80x9cHNMeOMexe2x80x9d refers to N-methoxyxe2x80x94N-methylamine.
xe2x80x9cMtrxe2x80x9d refers to 2,3,6-trimethyl-4-methoxyphenyl sulfonyl.
xe2x80x9cMtsxe2x80x9d refers to mesitylene-2-sulphonyl.
xe2x80x9cNMMxe2x80x9d refers to N-methylmorpholine, also called 4-methylmorpholine.
xe2x80x9cNMRxe2x80x9d refers to Nuclear magnetic resonance spectroscopy.
xe2x80x9c[O]xe2x80x9d refers to oxidation or oxidizing.
xe2x80x9cPAM resinxe2x80x9d refers to a resin prepared by coupling a phenylacetic acid derivative to aminomethyl polystyrene.
xe2x80x9cPCCxe2x80x9d refers to pyridinium chlorochromate.
xe2x80x9cPd/Cxe2x80x9d refers to palladium on charcoal, a hydrojunction catalyst.
xe2x80x9cPDCxe2x80x9d refers to pyridinium dichromate.
xe2x80x9cPdnxe2x80x9d refers to a pyridone moiety.
xe2x80x9cPhCOxe2x80x9d refers to benzoyl moiety.
xe2x80x9cPMA visualizationxe2x80x9d refers to visualization of a TLC plate with molybdophosphoric acid solution.
xe2x80x9cPmcxe2x80x9d refers to 2,2,5,7,8-pentamethylchroman-6-sulfonyl.
xe2x80x9cpMeBzlxe2x80x9d refers to 4-methylbenzyl.
xe2x80x9cpMeOBzlxe2x80x9d refers to 4-methoxybenzyl.
xe2x80x9cPrPentxe2x80x9d refers to 2-propylpentanoyl moiety.
xe2x80x9cPTSA catalystxe2x80x9d refers to para-toluene sulfonic acid.
xe2x80x9cPyr.SO3xe2x80x9d refers to pyridine sulfur trioxide complex.
xe2x80x9cRP-HPLCxe2x80x9d refers to reverse phase high pressure liquid chromatography.
xe2x80x9cRTxe2x80x9d refers to room temperature.
xe2x80x9cTBTUxe2x80x9d refers to 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate.
xe2x80x9ctBuxe2x80x9d refers to tert-butyl.
xe2x80x9cTEAxe2x80x9d refers to triethylamine.
xe2x80x9cTEMPOxe2x80x9d (as in 4-methoxy-TEMPO or TEMPO catalyst) refers to 2,2,6,6-tetramethylpiperidinyl nitroxide radical oxidizing reagent.
xe2x80x9cTFAxe2x80x9d refers to trifluoroacetic acid or the trifluoroacetic acid salt.
xe2x80x9cTFMSAxe2x80x9d refers to trifluoromethane sulfonic acid.
xe2x80x9cTHFxe2x80x9d refers to tetrahydrofuran.
xe2x80x9ctlcxe2x80x9d or xe2x80x9cTLCxe2x80x9d refer to thin layer chromatography.
xe2x80x9cTMSOTfxe2x80x9d refers to trimethylsilyltrifluoroacetate.
xe2x80x9cTosxe2x80x9d refers to p-toluenesulfonyl, also referred to as
xe2x80x9cTosylxe2x80x9d or xe2x80x9cTsxe2x80x9d.
xe2x80x9ctritylxe2x80x9d refers to triphenylmethyl.
xe2x80x9cZxe2x80x9d refers to a Benzyloxycarbonyl protecting group.